Abstract:
:Compound libraries provide a starting point for multiple biological investigations, but the structural integrity of compounds is rarely assessed experimentally until a late stage in the research process. Here, we describe the discovery of a neuroprotective small molecule that was originally incorrectly annotated with a chemical structure. We elucidated the correct structure of the active compound using analytical chemistry, revealing it to be the natural product securinine. We show that securinine is protective in a cell model of Huntington disease and identify the binding site of securinine to its target, protein disulfide isomerase using NMR chemical shift perturbation studies. We show that securinine displays favorable pharmaceutical properties, making it a promising compound for in vivo studies in neurodegenerative disease models. In addition to finding this unexpected activity of securinine, this study provides a systematic roadmap to those who encounter compounds with incorrect structural annotation in the course of screening campaigns.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Kaplan A,Stockwell BRdoi
10.1021/acsmedchemlett.5b00014subject
Has Abstractpub_date
2015-07-29 00:00:00pages
966-971issue
9issn
1948-5875journal_volume
6pub_type
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